An overview of dehydroepiandrosterone (EM-760) as a treatment option for genitourinary syndrome of menopause.

Introduction: Dyspareunia caused by vulvovaginal atrophy is a primary symptom of genitourinary syndrome of menopause (GSM), a chronic, progressive medical condition that results from estrogen and androgen deficiency at menopause. Dehydroepiandrosterone (DHEA, prasterone) is an endogenous precursor steroid hormone that is metabolized into both androgens and estrogens that has been recently been approved by the FDA for the treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy secondary to menopause.Areas covered: This is a comprehensive drug evaluation describing the chemical composition, pharmacokinetics, metabolism, clinical efficacy and safety of dehydroepiandrosterone (prasterone) in the treatment of dyspareunia and VVA secondary to menopause. Preclinical and clinical data suggesting further potential uses, benefits, and contraindications in the genitourinary health of postmenopausal women are also considered.Expert opinion: Intravaginal dehydroepiandrosterone (prasterone) is effective for the management of dyspareunia secondary to menopause and may be effective in the treatment of other types of sexual dysfunction that are secondary to menopause. Further studies should explore additional dosing regimens and different indications.

Nerve Growth Factor Is Associated With Sexual Pain in Women With Endometriosis.

Endometriosis is present in 1 in 10 reproductive-age women, and half experience deep dyspareunia (pelvic pain with sexual intercourse). Our objective was to investigate nerve growth factor (NGF) and its receptors (TrkA/p75NTR) in endometriosis-associated deep dyspareunia. A total of 32 women with endometriosis in the posterior pelvic compartment (cul-de-sac/uterosacrals) were included, either with (n = 17) or without (n = 15) deep dyspareunia symptoms confirmed by endovaginal ultrasound-assisted palpation on examination. Expression of NGF, TrkA, and p75NTR in the surgically excised cul-de-sac/uterosacral endometriosis was examined by immunohistochemistry and Histoscore blinded to pain phenotypes. Additionally, endometriotic stromal cells (ESCs; n = 3) from ectopic endometriosis lesions were cultured and incubated with/without NGF and/or Trk inhibitor K252a, followed by expression analysis of prostaglandin-endoperoxide synthase 2 (PTGS-2)/cyclooxygenase 2 (COX-2; reverse transcription quantitative real-time polymerase chain reaction and Western blot) and prostaglandin E2 (PGE2) secretion (enzyme-linked immunosorbent assay). We found that the immunointensity of NGF and TrkA, but not p75NTR, was significantly elevated in endometriotic stroma and epithelium from women with deep dyspareunia compared to women without deep dyspareunia. Nerve growth factor immunoreactivity in the stroma was also significantly associated with deep dyspareunia intensity and local nerve bundle density. In cultured ESCs, NGF significantly increased PTGS-2/COX-2 mRNA and protein levels as well as PGE2 secretion, and these effects could be abolished by pretreatment of Trk inhibitor K252a. In conclusion, elevated NGF levels were associated with deep dyspareunia in women with cul-de-sac/uterosacral endometriosis. This association may be mediated by increased nerve bundle density and by COX-2/PGE2 stimulation via Trk receptor. Nerve growth factor signaling may play an important role in endometriosis-associated sexual pain.

Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management.

Genitourinary syndrome of menopause, a new term for a condition more renowned as atrophic vaginitis, is a hypoestrogenic condition with external genital, urological, and sexual implications that affects >50% of postmenopausal women. Due to sexual embarrassment and the sensitive nature of discussing symptoms, genitourinary syndrome of menopause is greatly underdiagnosed. The most up-to-date literature pertaining to clinical manifestations, pathophysiology, etiology, evaluation, and management of genitourinary syndrome of menopause is comprehensively reviewed. Early detection and individually tailored pharmacologic (eg, estrogen therapy, selective estrogen receptor modulator, synthetic steroid, oxytocin, and dehydroepiandrosterone) and/or nonpharmacologic (eg, laser therapies, moisturizers and lubricants, homeopathic remedies, and lifestyle modifications) treatment is paramount for not only improving quality of life but also for preventing exacerbation of symptoms in women with this condition.

Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens--Findings from the Fourth International Consultation on Sexual Medicine.

INTRODUCTION: In recent years, multiple hormones have been investigated in relation to female sexual function. Because consumers can easily purchase products claiming to contain these hormones, a clear statement regarding the current state of knowledge is required. AIM: To review the contribution of hormones, other than estrogens and androgens, to female sexual functioning and the evidence that specific endocrinopathies in women are associated with female sexual dysfunction (FSD) and to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS: The literature was searched using several online databases with an emphasis on studies examining the physiologic role of oxytocin, prolactin, and progesterone in female sexual function and any potential therapeutic effect of these hormones. The association between common endocrine disorders, such as polycystic ovary syndrome, pituitary disorders, and obesity, and FSD also was examined. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the Grading of Recommendations Assessment, Development and Education system. RESULTS: There is no evidence to support the use of oxytocin or progesterone for FSD. Treating hyperprolactinemia might lessen FSD. Polycystic ovary syndrome, obesity, and metabolic syndrome could be associated with FSD, but data are limited. There is a strong association between diabetes mellitus and FSD. CONCLUSION: Further research is required; in particular, high-quality, large-scale studies of women with common endocrinopathies are needed to determine the impact of these prevalent disorders on female sexual function.

Nerve Bundles and Deep Dyspareunia in Endometriosis.

The etiology of deep dyspareunia in endometriosis is unclear. Our objective was to determine whether nerve bundle density in the cul-de-sac/uterosacrals (zone II) is associated with deep dyspareunia in women with endometriosis. We conducted a blinded retrospective immunohistochemistry study (n = 58) at a tertiary referral center (2011-2013). Patients were stringently phenotyped into a study group and 2 control groups. The study group (tender endometriosis, n = 29) consisted of patients with deep dyspareunia, a tender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 1 (nontender endometriosis, n = 17) consisted of patients without deep dyspareunia, a nontender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 2 (tender nonendometriosis, n = 12) consisted of patients with deep dyspareunia, a tender zone II on examination, and a nonendometriosis lesion (eg, normal histology) in zone II excised at surgery. Protein gene product 9.5 (PGP9.5) immunohistochemistry was performed to identify nerve bundles (nerve fibers surrounded by perineurium) in the excised zone II lesion. PGP9.5 nerve bundle density (bundles/high powered field [HPF]) was then scored by a pathologist blinded to the group. We found a significant difference in PGP9.5 nerve bundle density between the 3 groups (analysis of variance, F2,55 = 6.39, P = .003). Mean PGP9.5 nerve bundle density was significantly higher in the study group (1.16 ± 0.56 bundles/HPF [±standard deviation]) compared to control group 1 (0.65 ± 0.36, Tukey test, P = .005) and control group 2 (0.72 ± 0.56, Tukey test, P = .044). This study provides evidence that neurogenesis in the cul-de-sac/uterosacrals may be an etiological factor for deep dyspareunia in endometriosis.

A Practical Solution for Dyspareunia in Breast Cancer Survivors: A Randomized Controlled Trial.

PURPOSE: Dyspareunia is common in breast cancer survivors because of low estrogen. This study explored whether dyspareunia is introital pain, preventable with analgesic liquid. PATIENTS AND METHODS: In a randomized, controlled, double-blind trial, estrogen-deficient breast cancer survivors with severe penetrative dyspareunia applied either saline or 4% aqueous lidocaine to the vulvar vestibule for 3 minutes before vaginal penetration. After a 1-month blinded trial of patient-assessed twice-per-week tampon insertion or intercourse, all patients received lidocaine for 2 months in an open-label trial. The primary outcome was patient-related assessment of penetration pain on a scale of zero to 10. Secondary outcomes were sexual distress (Female Sexual Distress Scale), sexual function (Sexual Function Questionnaire), and resumption of intercourse. Comparisons were made with the Mann-Whitney U and Wilcoxon signed rank test with significance set at P < .05. RESULTS: In all, 46 patients, screened to exclude those with pelvic muscle and organ pain, uniformly had clinical evidence of severe vulvovaginal atrophy, dyspareunia (median pain score, 8 of 10; interquartile range [IQR], 7 to 9), increased sexual distress scores (median, 30.5; IQR, 23 to 37; abnormal, > 11), and abnormal sexual function. Users of lidocaine reported less pain during intercourse in the blinded phase (median score of 1.0 compared with saline score of 5.3; P = .007). After open-label lidocaine use, 37 (90%) of 41 reported comfortable penetration. Sexual distress decreased (median score, 14; IQR, 3 to 20; P < .001), and sexual function improved in all but one domain. Of 20 prior abstainers from intercourse who completed the study, 17 (85%) had resumed comfortable penetrative intimacy. No partners reported penile numbness. CONCLUSION: Breast cancer survivors with menopausal dyspareunia can have comfortable intercourse after applying liquid lidocaine compresses to the vulvar vestibule before penetration.

Effects of Glycine max (L.) Merr. soy isoflavone vaginal gel on epithelium morphology and estrogen receptor expression in postmenopausal women: a 12-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Evaluate the effects of vaginal administration of isoflavones derived from Glycine max (L.) Merr. as a treatment option for vaginal atrophy, on the morphology and expression of estrogen receptors in vaginal epithelium of postmenopausal women. METHODS: The double-blind, randomized, placebo-controlled, clinical trial. Sixty women were treated for 12 weeks with isoflavone vaginal gel 4% (1g/day) and a placebo gel. After 4 and 12 weeks, the vaginal atrophy symptoms were classified at none, mild, moderate and severe and the vaginal cytology were taken to determine the maturation value. Vaginal pH was measured at the beginning and end of therapy. Microbiopsies in vaginal fornix were performed before the treatment and after 12 weeks of treatment. RESULTS: Isoflavone vaginal gel was effective for relief of vaginal dryness and dyspareunia symptons and an increase in the intermediate and superficial cells was noted. The vaginal pH in the isoflavone group was 7.1 at baseline and 5.4 after 12 weeks, whereas in the placebo group there was no significant change. A significant increase in thickness after treatment was detected in the Isoflavone Group. The percentage of estrogen receptor positive cells in vaginal epithelium for the Isoflavone Group ranged from 58.5% at the beginning of treatment to 82.6% after 12 weeks. These results were superior to placebo gel. CONCLUSION: Glycine max (L.) Merr. at 4% vaginal gel on a daily basis in postmenopausal women led to improvements in vaginal atrophy symptoms, maturation values, vaginal pH, morphology and expression of estrogen receptors in vaginal epithelium. Isoflavones proved good treatment options for relief of vulvovaginal atrophy.

Profile of ospemifene in the breast.

Vulvar and vaginal atrophy (VVA) is a chronic, progressive medical condition prevalent among postmenopausal women, which produces symptoms such as dyspareunia, vaginal dryness, and vaginal irritation. Currently, the only prescription options are systemic and vaginal estrogen therapies that may be limited by concerns about long-term safety and breast cancer risk. Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause. Ospemifene, the first nonestrogen oral treatment for this indication, may provide an alternative to treatment with estrogen. Animal models with ospemifene suggest an inhibitory effect on growth of malignant breast tissue, but animal data cannot necessarily be extrapolated to humans. Clinical trials, including 3 long-term studies assessing the overall safety of ospemifene, support that ospemifene is generally well tolerated, with beneficial effects on the vagina, neutral effects on the breast, and minimal effects on the endometrium.

Biopsychosocial predictors of postmenopausal dyspareunia: the role of steroid hormones, vulvovaginal atrophy, cognitive-emotional factors, and dyadic adjustment.

INTRODUCTION: Although dyspareunia experienced after menopause is widely attributed to declining estrogen levels and vulvovaginal atrophy, critical reviews of the literature have suggested that these factors are incomplete as explanatory mechanisms. Little is known about psychosocial factors that may also be implicated in postmenopausal dyspareunic pain. AIM: To determine the extent to which levels of estrogens and progesterone, vulvovaginal atrophy, cognitive-emotional factors, and dyadic adjustment are predictive of postmenopausal dyspareunic pain intensity. METHODS: A total of 182 postmenopausal dyspareunia sufferers underwent a structured interview concerning sociodemographic status as well as medical and pain histories, gynecological examination, cytological evaluation, a blood draw, and answered a series of self-report questionnaires. Given the large number of genital and pelvic pain variables measured, a principal components analysis was undertaken to identify a smaller number of components representing meaningful dimensions of genital and pelvic pain. MAIN OUTCOME MEASURES: Pain severity ratings during intercourse were obtained using the McGill Pain Questionnaire. Pain ratings were also obtained during gynecological assessment. Serum estrone, estradiol, and progesterone levels were measured via immunoassay. The Vaginal Atrophy Index and maturation value were used to determine vulvovaginal atrophy severity. Participants completed the Pain Catastrophizing Scale, State-Trait Anxiety Inventory, The Beck Depression Inventory-II, and Dyadic Adjustment Scale. RESULTS: Hormone levels were not found to be consistent predictors of pain severity. Maturation value and cognitive-emotional variables (e.g., catastrophization, depression, anxiety) were significant predictors of vestibular pain, which affected over 90% of our sample. Relationship adjustment variables were inversely associated with pain severity within several genital locations. CONCLUSIONS: Results suggest that the traditional hypoestrogen and vulvovaginal atrophy conceptualization of postmenopausal dyspareunia is an insufficient explanatory model, and that pain is also influenced by cognitive, affective, and dyadic factors.

PPAR-gamma expression in peritoneal endometriotic lesions correlates with pain experienced by patients.

Endometriosis is a significant gynecologic condition that can cause both pain and infertility and affects up to 15% of women during their reproductive years. In peritoneal endometriotic lesions, the expression of peroxisome proliferation-activated receptor gamma, a nuclear receptor with antiinflammatory and neuroprotective roles, is positively correlated with the pain reported by patients.

Steroid receptor expression and morphology in provoked vestibulodynia.

OBJECTIVE: This study was undertaken to survey the steroid receptor expression and morphology in the vulvar vestibular mucosa in women with provoked vestibulodynia. STUDY DESIGN: Fourteen patients and 25 controls without oral contraceptives were included. Vestibular biopsy specimens were obtained and analyzed by using immunohistochemistry, followed by computerized image analysis of estrogen receptors alpha and beta, progesterone receptors A and B, glucocorticoid receptor, androgen receptor, and the proliferation marker Ki67. The morphology was estimated by measuring 4 parameters in the epithelium. RESULTS: There was a significantly higher expression of estrogen receptor alpha in both the epithelium (P = .04) and the stroma (P = .02) in the patient specimens compared with the controls. There were no significant differences in the other analyses performed. CONCLUSION: There is an increased expression of estrogen receptor alpha in the vestibular mucosa but the epithelial morphology seems unaffected in women with provoked vestibulodynia. Further studies regarding plausible associations to neurogenic inflammation are needed.